OBJECTIVE Uric acid is supposed but not yet determined to be associated with atherosclerosis. Uric acid is released from damaged cells to form urate crystal, which is recognized by the immune system to produce IL (interleukin)-1. Danger signals and IL-1 have been shown to play an important role in atherosclerosis. We determined whether the physiological level of soluble uric acid promotes inflammation and develops atherosclerosis. Approach and Results: The secretion of IL-1β from human peripheral blood mononuclear cells mediated by NLRP3 (NACHT, LRR, and PYD domain-containing protein 3) inflammasome was promoted by physiological levels in serum uric acid. This augmentation of inflammation was mediated by the regulation of the AMPK (AMP-activated protein kinase)-mTOR (mammalian target of rapamycin) mitochondrial reactive oxygen species and HIF-1α (hypoxia-inducible factor-1α) pathway. In both of uricase transgenic and xanthine oxidase inhibitor-treated mice, decreased levels of uric acid resulted in the activation of AMPK and attenuation of the development of atherosclerotic plaques. Further, acute uric acid reduction by the administration of benzbromarone in healthy humans for 2 weeks significantly decreased plasma IL-18-an inflammasome-dependent cytokine. CONCLUSIONS The data indicate that the development of atherosclerosis and inflammation is promoted by uric acid in vivo. Moreover, the lowering of uric acid levels attenuated inflammation via the activation of the AMPK pathway. This study provides mechanistic evidence of uric acid-lowering therapies for atherosclerosis.

中文翻译：

---

可溶性尿酸通过AMPK（AMP激活的蛋白激酶）介导的炎症促进动脉粥样硬化。

目的尿酸被认为但尚未确定与动脉粥样硬化有关。尿酸从受损的细胞中释放出来，形成尿酸盐晶体，而尿酸盐晶体被免疫系统识别为产生IL（白介素）-1。危险信号和IL-1已显示在动脉粥样硬化中起重要作用。我们确定了可溶性尿酸的生理水平是否促进炎症和发展动脉粥样硬化。方法和结果：血清尿酸的生理水平促进了NLRP3（NACHT，LRR和含PYD域的蛋白3）介导的人外周血单个核细胞分泌IL-1β。这种炎症的增强是通过调节AMPK（AMP激活的蛋白激酶）-mTOR（雷帕霉素的哺乳动物靶标）线粒体活性氧和HIF-1α（低氧诱导因子-1α）途径介导的。在尿酸酶转基因和黄嘌呤氧化酶抑制剂治疗的小鼠中，尿酸水平的降低导致AMPK的激活和动脉粥样硬化斑块的形成减弱。此外，通过在健康的人中施用苯溴马隆2周来减少急性尿酸，可显着降低血浆IL-18（炎性体依赖性细胞因子）。结论数据表明，体内尿酸可促进动脉粥样硬化和炎症的发展。此外，降低尿酸水平可通过激活AMPK途径来减轻炎症。